NKX3.1 Localization to Mitochondria Suppresses Prostate Cancer Initiation.

DOI
Publisher DOI
PubMed ID
33893149
Abstract
Mitochondria provide the first line of defense against the tumor-promoting effects of oxidative stress. Here we show that the prostate-specific homeoprotein NKX3.1 suppresses prostate cancer initiation by protecting mitochondria from oxidative stress. Integrating analyses of genetically engineered mouse models, human prostate cancer cells, and human prostate cancer organotypic cultures, we find that, in response to oxidative stress, NKX3.1 is imported to mitochondria via the chaperone protein HSPA9, where it regulates transcription of mitochondrial-encoded electron transport chain (ETC) genes, thereby restoring oxidative phosphorylation and preventing cancer initiation. Germline polymorphisms of NKX3.1 associated with increased cancer risk fail to protect from oxidative stress or suppress tumorigenicity. Low expression levels of NKX3.1 combined with low expression of mitochondrial ETC genes are associated with adverse clinical outcome, whereas high levels of mitochondrial NKX3.1 protein are associated with favorable outcome. This work reveals an extranuclear role for NKX3.1 in suppression of prostate cancer by protecting mitochondrial function. SIGNIFICANCE: Our findings uncover a nonnuclear function for NKX3.1 that is a key mechanism for suppression of prostate cancer. Analyses of the expression levels and subcellular localization of NKX3.1 in patients at risk of cancer progression may improve risk assessment in a precision prevention paradigm, particularly for men undergoing active surveillance.See related commentary by Finch and Baena, p. 2132.This article is highlighted in the In This Issue feature, p. 2113.
Date Issued
2021-09
Publication Type
Article
Subject(s)
Language(s)
en
Author(s)
Papachristodoulou, Alexandros
Panja, Sukanya
Margolskee, Elizabeth
Virk, Renu K
Milner, Teresa A
Martina, Luis Pina
Kim, Jaime Y
Di Bernardo, Matteo
Williams, Alanna B
Maliza, Elvis A
Caputo, Joseph M
Haas, Christopher
Wang, Vinson
De Castro, Guarionex Joel
Wenske, Sven
Hibshoosh, Hanina
McKiernan, James M
Shen, Michael M
Mitrofanova, Antonina
Dutta, Aditya
Abate-Shen, Cory
Additional Credits
Journal
Cancer discovery
Publisher
American Association for Cancer Research
ISSN
2159-8290
Access(Rights)
metadata.only
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